DK158728B - ANALOGY PROCEDURE FOR THE PREPARATION OF TRIAZOLONE DERIVATIVES - Google Patents

Description

in

DK 158728 B

The present invention relates to an analogue and method of preparing triazolone derivatives. More specifically, according to the invention, 2- [3- [4- (halo-phenyl) -1-piperazinyl] propyl] -5-ethyl-4- (phenoxyalkyl) -2H-1,2,4-triazole 3 (4H) -ones, 4- [3- [4- (halo-phenyl) -1-5-piperazinyl] propyl] -5-ethyl-2,4-dihydro-2- (phenoxyalkyl) -3H-1 , 2,4-triazol-3-ones, which can be used to treat depression.

U.S.A. Patent No. 3,857,845 to G, Palazzo discloses compound 1- [3- (4-metha-chlorophenyl-1-piperazinyl) propyl] -3,4-diethyl-2-1,2,4-triazoline 5-on with the structure shown below.

10 C9H ___N Cl Ί I / \ _τί

C2H5-V ^ N-CH2CH2CH2- \ / -W

15 || \ - /

ISLAND

Alternatively, the compound may be designated 2- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -4,5-diethyl-2H-1,2,4, -tri azole-3 (4H ) -on, and it is commonly called etoperidone.

Said U.S.A. Patent application discloses that the use of etoperidone has pharmacological properties typical of psychoactive substances, including sedation, reduced activity towards the experimental and lower motor activity. Furthermore, hypotensive and analgesic activity is indicated with possible use as an antianxiety agent and psychosedative agent in human therapy.

U.S.A. U.S. Patent No. 3,381,009 to G. Palazzo, et al.

30 discloses 1,2,4-triazole [4,3-a] pyridines of the following general formula

R O

DK 158728B

Wherein R is hydrogen or methyl and R 'is hydrogen, alkyl (1-4C), alkoxy (1-4C), or halogen. The compounds are reported to exhibit psychosedative, hypotensive and analgesic effects according to various animal studies. In terms of psychosocial action, the pharmacological profile includes behavioral effects such as sedation, decrease in motor activity, hypotonia, high-dose-induced muscular non-coordination and ataxia, as well as inhibition of conditioned reflexes in the rat. According to this patent, data on behavioral, adrenolytic and anti-serotonin effects suggest that the compounds 10 are similar to neuroleptics (major tranquilizers) such as chlorpromazine more than anxiolytics (minor tranquilizers) such as meprobamate. The pharmacological properties of one compound in particular, 2- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -1,2,4-triazole [4,3-a] pyridine-3 (2H) - on has been described in more detail by Sylvestrini, et al., International Journal 15 of Neuropharmacology, 7, 587-599 (1968). The aforementioned compound, commonly known as trazodone, has been extensively studied in humans and is considered an antidepressant equivalent in efficacy to imipramine but with fewer side effects (Fabre, et al., Current Therapeutic Research, 25, 827-834 (1979)). ).

In the broadest sense, the present invention relates to an analogous process for the preparation of piperazinylalkyl-1,2,4-triazole

3-ounces of formula I

C2n5 | 5 ------ TN

25 N v. 2.1 / \ 3 / '\ (A) B 0 A (B) wherein A is a group of formula - "" λ-ΌΚΤ 35 and B is a group of formula

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3. O and wherein n is an integer of 2-4, R is halogen, R 1 is hydrogen, halogen or 10 alkoxy and pharmaceutically acceptable salts thereof, the process of which is characterized by the characterizing part of claim 1. The term "halogen" or halo as used herein includes fluorine, odor and most preferably bromine and ehloro. The term alkoxy as used herein comprises from 1 to 4 carbon atoms such as methoxy, ethoxy, tert-butoxy and the like.

The pharmaceutically acceptable acid addition salts are those in which the anion does not significantly contribute to the toxicity or pharmacological activity of the salt and as such are the pharmacological equivalents to the bases of formula I. They are generally preferred for medical use. In some cases, the physical properties which make them more desirable for pharmaceutical formulation purposes such as solubility, lack of hygroscopicity, compressibility with respect to tablet formation, and compatibility with other ingredients with which the substance may be used for pharmaceutical purposes. The salts are prepared by reacting the base of formula I with the selected acid, preferably by contact in solution. They can also be prepared by metathesis or treatment with an ion exchange resin under conditions where the anion of one salt of the compound of formula I is replaced by another anion under conditions which allow separation of the desired compounds, such as by precipitation from solution or extraction in a solvent. , or elution from or retention on an ion exchange resin. Pharmaceutically acceptable acids for salt formation with the compounds of formula I include hydrochloric, hydrobromic, hydroiodic, citric, acetic, benzoic, mandelic, phosphoric, nitric, mucic, isethionic, palmitic, heptanoic and others.

In the most preferred embodiment, the present invention provides compounds of formula I wherein R is meta-chloro, R * is hydrogen and n is the total number 2.

The compounds of formula I are valuable pharmacological agents

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4 with psychotropic properties. In this regard, they exhibit selective effects on the central nervous system, accompanied by antidepressant activity according to conventional in vivo test systems, such as those listed below.

5

Behavior Test Reference

Suppression by Conditioned Albert et al., Pharmacologist, Avoidance Reaction (CAR) 4, 152 (1962).

10

Inhibition of Reserpine Niemeegers, Industrial -ptosis in Mice Pharmacology, Vol. 2 - Anti- (antidepressant) depressants, Ed. by S. Fiel ding and H. Lal, pp. 73-98, 15 Futura, New York, N. Y., (1975).

Potentiation of Alcohol Hypnosis in Mice (Sedative) In these tests, 2- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5- ethyl 4- (2-phenoxyethyl) -2H-1,2,4-triazole-3 (4H) -one CAR in the rat and prevented but did not reverse reserpine ptosis in mice. Such activity is characteristic of most clinically useful anti-depressants. Sedation is a common side effect of antidepressants. In this regard, compound 1a showed only minimal activity in potentiating all alcohol hypnosis in mice, suggesting a relative lack of this undesirable reaction.

As further indication of the psychotropic activity and specificity of the compounds of the invention, known in vitro central nervous system receptor binding method may be used. Certain compounds (usually referred to as ligands) have been identified as preferentially binding to specific high-affinity points in brain tissue regarding psychotropic activity or potential for side effects. Inhibition of radiolabelled ligand binding to such specific high-affinity points 35 is considered a measure of a compound's ability to cause similar central nervous system function or cause side effects in vivo.

The following tests as well as others may be used to develop a profile for the psychotropic activity of the present compounds.

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5

Receptor Binding Sample Reference

dopamine

Burt, et al., Molec, Pharmacol, 12,500 (1976); Science, 196, 326 (1977);

Creese, et al., Science, 192, 481 (1976).

Cholinergic Yamamure, et al., Proc. Natn. Acad.

10 Sci. U.S.A. 71, 1725 (1974).

Alpha-receptor Crews, et al., Science 202: 322 (1978).

Rosenblatt, et al., Brain Res. 160: 15 186 (1979).

O'Prichard, et al., Science 199: 197 (1978).

U'Prichard, et al., Molec. Pharmacol.

13: 454 (1977).

20

Serotonin Type 2 Peroutka and Snyder, Molec. Pharma col. 16: 687 (1979).

According to the preceding tests, compounds of formula I wherein R is meta-chloro and R 'are hydrogen serotonin binding and were relatively inactive with respect to dopamine receptor binding, cholinergic receptor binding and alpha receptor binding. The latter is particularly significant in that high affinity drugs for alpha receptors over serotonin type 2 receptors are likely to cause side effects such as sedation and blood pressure lowering. Therefore, the present compounds and especially the above most preferred embodiments are considered as improved antidepressants with minimal potential for side effects.

The biological activity of a representative selection of the compounds of formula I is set out below

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6 _____ |

Cb ω <u 0 a ω> i u eh 0 • η β Ό · Η cd · Ρ. ^ 54 O S S 2 - 54 C «· C 2 44 CD c ιί ra o M 1/1 i LO r- - - ^ tn tn M O ^ ^ β C H m 10 ^ Η · Η 54 HCi -.

(D β 04, Λ Ή E4> • Η Λ S S β I β O in H 4-1 · - '

O β „Η O 4-> · γ4 H + J

'OM β β OO) - W β · v, 44 3 ° · _ ^ SS <£ β <D ^> · 2 * ε o »to o ^ S' c„ • ri on in ac ® m 'δ cr ° '

H β H ™ ^ ° S

β 4-1 -. F- -¾1 ad) Pi ^ ro Λ ftn <β φ u ω β -

Cr = go <? ό o „Φ w jzcj i s. <n <o H o ro O ro E -

i — I I i 04 - tN - JN

m 2 cm S 04 m S

4 tar- «» - * «- r> I S vU ^ w µι 'u in O O w 0 ---.- w V - 1

11 i 04 O! O I · - “Z

tc * 2, S rH 2 V-, r4 g! α · ϋ f> ° S f> = g Λ / y g I s Λζ 'E / -27 · os) i jS 04 I cm i 2 ro β! z \ _rO S 04 S 04 O ~

3 'X / = ° O ~ O ~ jn OJ

rn / 2 ro OJ ro 04 S S

Η 'i SE SS O O

(1) 04 04 O «3 O O w

I7-J E »-. '- - · I

C O ~ oi I I O

-β Ό S C O V.

0 rJ? P ° 0 fS "^

* 7 ο V kAs A

(TY s __ ·? __

7 DK 158728 B

In CM

ft <D Q)

O ft <D> 1 U And O

• H β Ό · Η id -µ ^ UU = "ξ 5« SCO o g u> tPfta · »£ * β C H ^ ^ • Η 'ri J-f Π3 -.

0 ΰ n • η λ a Λ Μ I β Ο in Η -Ρ ^

• Η I

Ό Μ β 0) S “s s tu γ ^ <Η ° id 7 ^ tn id Cn Cd !? ?

Td row ^ "β β O · (-> o O β ~ O g o Η · IX - 0) + J β ft t n Q) o ·. Λ Φ U -Η ^ Λ Λ U 0) +>

ft β M O

ft 0 id m

β · Η Φ Q

[Q-P MW

_ g_ V v Q? H S S *.

M ro t>

m ^ T <H

i «2-5. y p Β II Vo r 0. ] Lg '

d II V? - _T

S! U 'g o n e / T ro *

u n «SO

ω a - u T

cq o nc i o) ΐ υ) —v • d o y / \ β \\ //.

• Η <3_ Y_7 1

] 3 p

“Ϋ __-_—- X ..., -,.,. = - = - = - i

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8

According to the invention, the 2-piperazinylalkyl-1,2,4-triazol-3-ones of formula I are prepared by the following analogue method comprising treating a 2-piperazinylalkyltriazolone of formula II

c2hs n / =) (8Ύ0 (II) 10 wherein R is halogen bonded at the 2-, 3- or 4-position of the phenyl ring, with a suitable all potassium metal base such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate to form a any potassium salt thereof and then alkylation of the alkali metal salt of the compound of formula II with a phenoxyalkyl halide of formula VII, wherein R 1 is as defined above, n is an integer 2-4 and "X" comprises halogen, preferably chlorine or bromine. or a suitable leaving group such as sulfate, phosphate, tosyl at, mesylate and the like (VII) 25

It is to be understood that Formula II shows a tautomer of a compound of an alternative tautomeric form of formula ΙΓ ^ TT ', v 30 s _,'! - ch, ch, ch2-n P \ j il “**> -io (II '> 4-piperazinylacyl-1,2,4-triazol-3-ones of Formula I are prepared by the following procedure which comprises reacting a 4-piperazinylalkyltriazolone of Formula IIa

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9 C2H5 I '- * j' ThCjrla, * <* 'Ym 5' - / 0 (Ha) wherein R represents halogen bonded at the 2-, 3- or 4-position of the phenyl ring, with a phenoxyalkyl halide of formula (VII) wherein Rj is as defined above, n is an integer from 2-4 and "X" comprises halogen, preferably chlorine or bromine, or a suitably leaving group such as sulfate, phosphate, tosylate , mesylate and the like, in the presence of a suitable all potassium base such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate in a reaction inert solvent such as xylene or acetonitrile and the like.

Standard ablation procedures are used to perform the foregoing reaction, such as those described for the alkylation step of the Gabriel synthesis - S. Gabriel, Ber. 20, 2224 (1887). In the present case, the reactants are combined in a solvent inert for the reaction at temperatures ranging from ca. 50 ° C to 200 ° C. Acetonitrile and xylene are particularly preferred solvents for carrying out the reaction, but other solvents which do not adversely affect the reaction or reactants can be used. In this regard, solvents such as benzene, toluene, dimethyl formamide, n-butanol and the like are suitable. The reaction time varies to some extent, depending on the solvent and temperature chosen. For example, at lower temperatures, longer reaction times are required, while all cooling is completed in a shorter time at higher temperature. In the case of acetonitrile or xylene, optimal yields are obtained for a reaction time of 8 to 68 hours.

A preferred process for the preparation of compounds of formula I comprises reacting a piperazinylalkyltriazolone of formula 10

DK 158 72 8 B

II or IIa with a phenoxyalkyl halide of formula (VII) in the presence of an all potassium carbonate such as potassium carbonate or sodium carbonate in acetonitrile.

The 2-piperazinylalkyltriazolone intermediates of formula (II) 5 are preferably obtained by alkylation of hydrazine with a 1- (halophenyl) -4- (3-halopropyl) piperazine to form a 1- (halophenyl) -4- (3-hydrazine). propyl) piperazine of formula (III)

NH9VH-CH, CH, Clt, -W U-f ~ K

(III) 15, which is then condensed with N-ethoxycarbonylthiopropionamide 0 0 II µl (CH 2 CH 2 Cl-NH-COCgHg) in a reaction inert solvent at elevated temperature. All canals, such as ethanol, are particularly preferred as solvents where the reaction is conveniently carried out at reflux temperature. Other suitable solvents include acetone, acetonitrile, ethyl acetate, dimethyl formamide, ethers such as tetrahydrofuran and the like.

The 4-piperazinylalkyl triazolone intermediates of formula (IIa) are prepared by heating N-ethoxycarbonylthiopropionamide with hydrazine in ethanol to give the triazolone compound of formula (IV)

C2H5 I

HU. / NH

'V 1

30 O

(IV)

which is then alkylated with a 1- (halophenyl) -4- (3-halopropyl) -piperazine of formula V

- / - \

35 * -Q

(V)

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wherein R is halogen and X comprises halogen, preferably chlorine or bromine, or an appropriate leaving group such as sulfate, phosphate, tosylate, mesylate and the like, in the presence of an appropriate all potassium base such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide and the like in a solvent inert for the reaction. Laboratory procedures and solvents (preferably acetonitrile) previously described as useful for the alkylation of the intermediates of formula IIa with the phenoxyalkyl halides of formula VII are used.

Another useful process for preparing intermediate products of Formula II and IIa involves heating N

carbonylthiopropionamide with hydrazine in ethanol to give the triazolone compound of formula IV

15 h: NH

The V 2 O (IV) 20 is then alkylated with a 1- (halophenyl) -4- (3-halopropyl) piperazine compound in xylene at reflux temperature. Compared to the previously described preparation of intermediates of formula II, this process is not as satisfactory as the triazolone (IV) is randomly alkylated at the 2- and 4-positions leading to lower yields of the desired piperazinylacyltriazolone (II). For example, the reaction of triazolone (IV) with 1- (3-phenyl) -4- (3-chloropropyl) piperazine in xylene under reflux provides the following compounds (isolated as hydrochloride salts) as secondary products in addition to the desired piperazinylal cool triazolone flour limb product. formula (II) wherein R is metachloro.

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12

Secondary products n / 1 s A = -CH 2 CH 2 CH 2 -N 2 'HCl cu N 4- [3- [4- (3-chlorophenyl) -1-2 piperazinyl] propyl] -5-ethyl-2,4- 10 N-1 µm-dihydro-3H-1,2,4-triazol-3-one, (} hydrochloride; mp 210-212 ° C.

(dec.) chd 2,4-bis- [3- [4- (3-chlorophenyl) -2-piperazinyl] propyl] -5-ethyl-2H-1,2,4-tri azole -3 (4H) -one, o hydrochloride; mp 206-208 ° C.

(dec.) 20 An alternative method of preparing a compound of formula

C2H5T = N

I I

25 O

comprises condensation of a 1- (halophenyl) -4- (3-hydrazinopropyl) -piperazine of formula III with an N-phenoxyethyl-N-ethoxycarbonylthiopropionamide of formula V wherein R 1 is as defined above and n is 2- 4th

R1 ai3cu2c = s ^ \ __ 0- (CUo) n-N-c ^ C2H5 \ I “35 (V)

The condensation is carried out in a suitable solvent for the reaction, such as ethanol, as previously described for the preparation of

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13 piperazinylal cool the triazolones of formula (II). The intermediate of formula V can be obtained by standard methods such as condensation of methyl di-thiopropionate with an N- (phenoxyalkyl) ethyl carbonate under basic conditions or alkylation of N-ethoxycarbonylthiopropionamide with a phenoxyalkyl halide of formula VII in the presence of an alkali metal base.

The above-described processes for preparing the compounds of formula C2H5T =?

10 I I

b / BYVa o

15 is a unitary process which comprises condensation of an amide of formula VI

s o

Il 'i

CH - CH2 C-N-COC nH

3 2 i 2 b R1 20 (VI)

wherein R 1 represents hydrogen or R 2 -phenoxyalkyl of 2 to 4 carbon atoms with a 1- (halophenyl) -4- (3-hydrazine propyl) piperazine of formula III

/ \ / = vR

iw2W-ch2ch2ch2-n? \ j

30 '- (III) wherein R represents halogen in a reaction inert solvent at elevated temperatures to form compounds of formula I wherein R' represents R 2 -phenoxyalkyl and the compound of formula II wherein R 'represents hydrogen, and subsequent alkylation of a compound of formula II with a phenoxyalkyl halide of formula VII in the presence of

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14 and all the metal base.

An even more preferred method of preparing a compound of the formula

C2H5 “l '...... ~ N

Yes

ISLAND

comprises alkylation of a phenoxyalkyl triazolone of formula VIII

10

Rx _ C2H5- | = ^ T) -0- (CH2) n-N \ / Ml 'v._y j [ϋ 15 (VIII) i

wherein R 1 represents hydrogen, halogen or alkoxy and n is an integer 2-4 with a 1- (halophenyl) -4- (3-halopropyl) piperazine of formula IX

20

/ ~ λ R

(IX) wherein R represents halogen and. X comprises halogen, preferably chlorine or Ter bromine or a suitable leaving group such as sulfate, phosphate, tosylate, mesylate and the like, in the presence of a suitable all potassium base such as sodium carbonate, potassium carbonate, potassium hydroxide and preferably sodium hydroxide in one for the reaction. inert solvent. The term "a solvent inert for the reaction" refers to any protic or aprotic solvent or diluent which is not substantially involved in any reaction. The laboratory procedures and solvents previously described as useful for the alkylation of intermediates of formula II with phenoxyalkyl halides of formula VII are used. In the present case preferred

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15 all channels, especially isopropanol.

The aforementioned preferred process for the preparation of compounds of formula I from triazolone intermediates of formulas II and VIII can be considered as embodiments of a unit process comprising 5 µl of cooling a compound of formula X

C2 "5-J—- * | _

(A1) (B'J

10 T

(X) wherein A 'is hydrogen or the above group A 15 B' is the hydrogen or phenoxyalkyl group

Ri.

Wherein "Rj" has the meaning given above, "n" is an integer 2 to 4 and one of A 'or B' must be hydrogen, with an alkylating agent 30 of formula VII or IX.

The compounds of the process can be used to treat a depression afflicted mammal by administering to the animal a therapeutically effective antidepressant amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof. An effective dose ranges from 0.01 to 40 mg / kg body weight, the dosage being dependent on the effects sought, modes of administration and, to some extent, the particular compound selected.

Systemic administration refers to oral, rectal and parenteral (i.e.

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16 intramuscular, intravenous and subcutaneous). In general, it will be found that by oral administration of one of the compounds of the present invention, a greater amount of the active ingredient is required to produce the same effect as a smaller parenterally administered amount. In accordance with good clinical practice, it is preferred to administer the compounds of the process at a concentration level which will cause effective antidepressant effects without causing any harmful or undesirable side effects.

The compounds of the process may be administered for antidepressant purposes either as individual therapeutic agents or as mixtures with other therapeutic agents. Therapeutically, they are generally administered as pharmaceutical compositions comprising an antidepressant amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Pharmaceutical preparations which provide from ca. 1 to 500 mg of the active ingredient per day. unit dose is preferred and conventionally prepared as tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs and aqueous solutions.

The nature of the pharmaceutical composition will, of course, depend on the desired route of administration. For example, oral preparations may be in the form of tablets or capsules and may contain conventional excipients such as binders (e.g., syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (e.g., lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine), lubricants (e.g., magnesium stearate, talc, polyethylene glycol or silica), disintegrants (e.g., starch), and wetting agents (e.g., sodium lauryl sulfate). Solutions or suspensions of a compound of formula I with conventional pharmaceutical vehicles are used for parenteral preparations such as an aqueous solution for intravenous injection or an oily suspension for intramuscular injection.

The process of the invention and the compounds prepared are illustrated in more detail in the following examples. Nuclear Magnetic Resonance Spectra (NMR) refer to chemical shift values down field (δ), expressed as 35 parts per million (ppm) relative to tetramethylsilane as a reference standard. The relative area reported for the different switching values corresponds to the number of hydrogen atoms in the individual substituent and the nature of the switches in terms of multiplicity is

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17 reported as broad singlet (bs), multiplet (m), triplet (t) or quadroplet (q) with coupling constant reported where relevant.

The format is NMR (solvent): 6 (relative area, multiplicity, J value). The abbreviations used are DMSO-dg (deuterodimethyl sul foxide), 5 IR (infrared), and KBr (potassium bromide).

Example 1 2- [3- [4- (3-Chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-1H-1,2,4-triazole -3 (2H) -one * (Ila) 10

C CU25 “] - = j j - HNx ^^ N N-CH ?CH7CH₂-N ^ _J (a) 1- (3-chloropropyl) -4- (3-chlorophenyl) piperazine hydrochloride.

A 50% sodium hydroxide solution (430.6 g, 5.333 mol) is added dropwise to a stirred solution of 1- (3-chlorophenyl) piperazine, hydrochloride 20 (502.0 g, 2.153 mol) and 1-bromo-3-chloropropane (339.0 g, 2.153 mol) in 435 ml of water and 535 ml of acetone while maintaining a temperature of 0-10 ° C.

Stirring is continued for a period of 16 hours at room temperature, and the upper organic phase is then separated and concentrated under reduced pressure. The residual residual oil is collected in 500 ml of acetone, filtered and the filtrate is concentrated under reduced pressure to an oily residue which is dissolved in boiling, dilute hydrochloric acid (1.67 liters of water plus 280 ml of concentrated HCl, 3.36 mol). The oil, which initially separates from the cooled acidic solution, solidifies upon standing and is collected, rinsed with cold water and air-dried. Crystallization of this material from water using activated charcoal gives 438.4 g (66%) of 1- (3-chloropropyl) -4- (3-chlorophenyl) piperazine, hydrochloride, mp 196.5-198.5 ° C .

Alternatively called 2- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -35-5-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one.

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is (b) 1- (3-chlorophenyl) -4- (3-hydrazine propylpiperazine).

Hydrazine hydrate (10.7 g, 0.184 mol) in 20 ml of ethanol is slowly added to 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine hydrochloride (9.29 g, 0.03 mol) in 20 ml of ethanol . After refluxing the mixture for a period of 3 hours, the solvent is removed under reduced pressure and 20 ml of water is added to the residue. A 50 ml portion of tetrahydrofuran is added to the aqueous mixture, which is then saturated with potassium hydroxide tablets using cooling in an ice bath. The tetrahydrofuran phase is separated, dried over magnesium sulfate and concentrated under reduced pressure to give 7.4 g (92%) of 1- (3-chlorophenyl) -4- (3-hydrazinopropyl) -piperazine, which is used without further purification in the following step. .

(c) 2- [3- [4- (3-Chlorophenyl) -1-piperazine] propyl] 5-ethyl-1H-1,2,4-triazol-3 (2H) -one.

A solution of 1- (3-chlorophenyl) -4- (3-hydrazine propyl) piperazine (19.6 g, 0.073 mol) in 90 ml of ethanol is added to N-ethoxycarbonylthiopropionamide (12.13 g, 0.073 mol) 30 ml of ethanol. The mixture is refluxed for a period of 16 hours during the development of hydrogen sulfide increase then concentrated under reduced pressure. Crystallization of ethanol residual material yields 18.3 g (72%) of 2- [3- [4- (3-chloro-phenyl) -1-piperazinyl] -propyl] -5-ethyl-1H-1,2, 4-triazole-3 (2H) -one, mp 79-81 ° C.

Addition of ethanolic hydrogen chloride to a sample of the base in ethanol with precipitation of the salt with ether gives 2- [3- [4- (3-chloro-phenyl) -1-piperazinyl] propyl] -5-ethyl-1H-1, 2,4-triazol-3 (2H) -one, hydrochloride, mp 165-167 ° C.

Analysis calculated for C CyH₂ClClNgO.HCl: C, 52.86; H, 6.53; N, 18.13. found; C, 52.72; H, 6.44; N, 17.96.

NMR (DMSO-d6): 1.15 (3H, t, 7.3 Hz), 2.16 (2H, m), 2.43 (2H, q, 7.3 Hz), 3.18 (8H , m), 3.68 (4H, m), 6.89 (3H, m), 7.24 (1H, m), 11.49 (1H, bs).

IR (0.5% KBr, cm -1); 770, 940, 1255, 1440, 1485, 1595, 1690, 2570,. 2980th

35

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19

Example 2 2- [3- [4- (3-Chlorophenyl) -1-piperazinyl] propyl-5-ethyl-4- (2-phenoxyethyl) -2H-1,2,4-triazol-3 (4H) -one * 5

c * l = t ΛΛ / -T

(A) Reaction in xylene.

Sodium hydroxide (2.08 g, 0.052 mol) in 10 ml of water is slowly added to 2-15 [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-1H-1,2,4 -Triazole-3 (2H) -one (18.2 g, 0.052 mol) in 150 ml of hot ethanol with stirring. When the mixture is complete, distillable material is removed under reduced pressure. Ethanol is added to residual material and removed under reduced pressure and the process is repeated until the sodium salt of 2- [3- [4- (3-20 chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-1H-1,2 4-Triazole-3 (2H) -one is obtained as a hard solid.

The sodium salt is pulverized, suspended in 200 ml of xylene and mixed with phenoxyethyl bromide (10.4 g, 0.052 mol) in 20 ml of xylene. The resulting mixture is refluxed with stirring for a period of 25 hours and the hot reaction mixture is filtered. The filtrate is concentrated under reduced pressure and residual material is collected in ether. Insoluble matter is collected and the ether filtrate concentrated to give 22.9 g (94%) of 2- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-4- (2-phenoxyethyl) ) -2H-1,2,4-triazole-3 (4H) -one as the free base. Purification of the product is carried out by making a solution of the free base acidic in ethanol with ethanol in hydrogen chloride and crystallization to give hydrated (0.25 mol) 2- [3- [4- (3-chlorophenyl) -1-piperazinyl ] propyl] -5-ethyl-4- (2-phenoxyethyl) -2H-1,2,4-triazol-3 (4H) -one hydrochloride, mp 175-177 ° C (30.7% yield) .

Calcd for C Cl ClNgOg.HCl.1 / 4 ^O: C, 58.77; H, 6.61; N, 13.71. Found: C, 58.61; H, 6.48; N, 13.68.

NMR (DMSO-d 6): 1.20 (3H, t, 7.5 Hz), 2.16 (2H, m), 2.66 (2H, q, 7.5 Hz), 3.27 (8H, m), 3.74 (4H, m), 3.96 (2H, t), 4.17 (2H, t), 6.96 (6H, m),

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7.29 (3H, m), 11.50 (1H, bs).

IR (0.5% KBr, cm -1): 755, 940, 1235, 1440, 1490, 1595, 1710, 2580, 2940.

Alternatively called 2- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-2,4-dihydro-4- (2-phenoxyethyl) -3H-1,2,4 triazol-3-one.

A sample of non-hydrated 2- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-4- (2-phenoxyethyl) -2H-1,2,4-triazole -3 (4H) -10 -one hydrochloride obtained according to the above process melted at 175-177 ° C.

Analysis calculated for C 25 H 32 ClN 5 ° 2 * HCl: C, 59.29; H, 6.57; N, 13.83. Found: C, 58.98; H, 6.44; N, 13.58.

NMR (DMSO-d6): 1.20 (3H, t, 7.5 Hz), 2.14 (2H, m), 2.65 (2H, q, 7.5 Hz), 3.25 (8H »M), 3.72 (4H, m), 3.95 (2H, t), 4.16 (2H, t), 6.91 (6H, m), 7.25 (3H, m), 11 , 61 (1H, bs).

C 13 NMR (DMSO-d 6): 9.65, 18.40, 22.90, 40.57, 41.89, 44.73, 50.31, 52.92, 64.95, 114.06, 114.30 , 115.21, 119.12, 120.93, 129.53, 130.55, 133.94, 147.92, 150.78, 153.15, 157.87.

Ir (0.5% KBr, cm -1): 750, 940, 1235, 1440, 1485, 1595, 1710, 2570, 2930.

(b) Reaction in acetonitrile with potassium carbonate.

A mixture of 2- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-1H-1,2,4-triazol-3 (2H) -one (15 g, 0.043 mole), phenoxyethyl bromide (8.62 g, 0.043 mole), potassium carbonate (11.9 g, 0.086 mole) and traces of potassium iodide in 100 ml of acetonitrile are refluxed for a period of 64 hours. The reaction mixture is filtered, the filtrate is concentrated under reduced pressure and residual material is collected in ether and filtered. Concentration of the ethereal filtrate gives 18.35 g (91%) of the free base 2- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-4- (2) phenoxyethyl) -2H-l, 2,4-triazol-3 (4H) -one. The free base is converted to the hydrochloride in ethanol using ethanol in so-called hydrogen chloride and crystallized from ethanol to give a yield of 53% of analytically pure 2- [3- [4- (3-35 chlorophenyl) -1-piperazinylpropyl]. -5-ethyl-4- (2-phenoxyethyl-2H-1,2,4-triazol-3 (4H) one, hydrochloride, mp 175-177 ° C.

Analysis calculated for C CHH ^ gClNgOg.HCl: C, 59.29; H, 6.57; N, 13.83. Found: C, 59.42; H, 6.68; N, 13.52.

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21 NMR (DMSO-d 6): 1.20 (3H, t, 7.5 Hz), 2.15 (2H, m), 2.65 (2H, q, 7.5 Hz), 3.25 (8H , m), 3.72 (4H, m), 3.95 (2H, t), 4.16 (2H, t), 6.93 (6H, m), 7.27 (3H, m), 11 , 61 (1H, bs).

IR (0.5% KBr, cm -1): 755, 940, 1240, 1440, 1490, 1595, 1710, 2580, 2940,

Example 3 2- [3- [4- (3-Chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-2,4-dihydro-4- (3-phenoxypropyl) -3H-1,2,4-triazol-3-one C2h5- = ij / ci ^ -0- (Cll2) 3 -ilv ^ / N- (Cll2) 3-N N - ^ _ j> II \ - /

ISLAND

15

A mixture of 2- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-1H-1,2,4-triazol-3 (2H) -one (3.86 g , 0.01 mole), 3-phenoxy-propyl bromide (2.15 g, .01 mole) of potassium carbonate (4.15 g, 0.01 mole) and 20 traces of potassium iodide in 50 ml of acetonitrile are refluxed for a period of time. 65 hours. The reaction mixture is filtered, the filtrate is concentrated under reduced pressure and residual material collected in ether and filtered. Solvent is removed and further purification is carried out by sequential conversion of the free base to the hydrochloride salt and then to the free base which is chromatographically treated using a silica / methanol / chloroform column as eluant. Free base, obtained by the chromatographic separation, is converted to the hydrochloride salt in ethanol using ethanolic hydrogen chloride to give 1.17 g (22% yield) of analytically pure 2- [3- [4- (3-chlorophenyl) -30 L]. piperazinyl] propyl] -5-ethyl-2,4-dihydro-4- (3-phenoxypropyl) -3H-1,2,4-triazol-3-one hydrochloride, mp 145-147 ° C.

Analysis calculated for 26 26 34 34 1 1 5 5 V V: C, 60.00; H, 6.78; N, 13.46. Found: 60.27; H, 6.82; N, 13.67.

NMR (DMSO-d 6): 1.15 (3H, t, 7.2 Hz); 2.10 (4H, m); 2.55 (2H, q, 7.2 Hz); 3.18 (6H, m); 3.75 (8H, m); 3.99 (2H, t, 6.0 Hz); 6.94 (6H, m); 7.27 (3H, m); 11.70 (1H, bs).

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22

Example 4 2- [3- [4- (3-ChlorophenylM-Piperazinynopropyl] -5-ethyl-2,4-dihydro-4- (4-phenoxybutyl) -3H-1,2,4-triazol-3-one

/ = u εΛΊ ^ 1 / „Λ _A

Q-0- (CH2) 4- »Μ- (αι2) 3-Ν ^ _J - \ J

o 10

A mixture of 2- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-1H-1,2,4-triazole-3- (2H) -one (3.86 g , 0.01 mole) of 4-phenoxybutyl bromide (2.29 g, 0.01 mole) of potassium carbonate (4.15 g, 0.01 mole) and traces of potassium iodide in 50 ml of acetonitrile is refluxed for a period of 65 hours.

The reaction mixture is filtered, the filtrate is concentrated under reduced pressure, and residual material is collected in ether and filtered. Concentration of ethereal filtrate gives the free base. Conversion of the free base to the hydrochloride salt in ethanol with ethanolic hydrogen chloride and crystallization of the salt from ethanol gives analytically pure 2- [3- [4- (3-chloro-phenyl) -1-piperazinyl] propyl] -5-ethyl-2 , 4-dihydro-4- (4-phenoxybutyl) -3H-1,2,4-triazol-3-one hydrochloride, mp 152-154 ° C.

Analysis calculated for C 27 H 36 ClN 5 ° 2 * HCl: C, 60.68; H, 6.98; N, 13.11. Found: C, 60.70; H, 6.86; N, 13.25.

NMR (DMSO-d 6): 1.19 (3H, t, 7.4 Hz); 1.74 (4H, m); 2.19 (2H, m); 2.58 (2H, q, 7.4 Hz); 3.19 (6H, m); 3.70 (6H, m); 3.99 (4H, m); 6.92 (6H, m); 7.26 (3H, m); 11.70 (1H, bs).

Example 5 5-Ethyl-4- (2-phenoxyethyl) -2H-1,2,4-triazol-3 (4H) -one (Villa, n = 2)

C2H5 - = * J

Q-o- (w2) 24 j "'35 υ

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23 (a) 3-Phenoxypropionylhydrazide, hydrochloric acid

Ethyl 3-phenoxypropionate (1481.0 g, 7.62 mol) obtained according to R.

Hall, et al., J. Chem. Soc., 2035 (1949) is stirred in an ice bath with the addition of 95% hydrazine (308.3 g, 9.14 mol). A precipitate is formed and the mixture is left at room temperature for 5 hours, then cooled for 16 hours and filtered to give 1128.0 g of white solid (82.1% yield) of 3-phenoxypropionylhydrazide. Precipitation of the hydrochloride salt is carried out by dissolving 3-phenoxypropionylhydrazide (2000.6 g, 11.1 mol) in 5 liters of methylene chloride. The solution is stirred and cooled in an ice bath while dissolving anhydrous hydrogen chloride in the mixture to pH 3. Solid is collected, rinsed with methylene chloride and air dried to give 2100.0 g (87.1% yield) of 3-phenoxypropionylhydrazide, hydrochloride , mp 145-156 ° C.

(B) 1-propionyl-4- (2-phenoxyethyl) semicarbazide.

A mixture of 3-phenoxypropionylhydrazide, hydrochloride (938.9 g, 4.333 moles), 6.8 kg of ice water and 3.4 liters of toluene is stirred in an ice bath while a solution of sodium nitrite (328.6 g, 4.763 moles) in 1 4 liters of water are added over a period of 10 minutes. The mixture is stirred for 0.5 hour at 20 ° C, CELITE is added and the mixture is filtered through a CELITE bed. The filtrate layers are separated and the aqueous layer is extracted with two 400 ml portions of toluene. The combined toluene extracts are dried over magnesium sulfate, filtered and the toluene solution of 3-phenoxypropionyl azide added over a 1.5 hour period to a flask 25 heated on a steam bath under a nitrogen atmosphere with stirring. After the addition, decomposition of the azide to the phenoxyethyl isocyanate intermediate is completed by heating and stirring until gas evolution stops. The clear yellow solution is cooled to 20 ° C and propionylhydrazide (381.8 g, 4.333 mol) obtained according to T. Rabini, et al., J. Org. Chem., 30, 2486 (1965) to be added in a portion under stirring. Stirring is continued and the reaction mixture is cooled to 10 ° C and filtration gives 792.2 g (72.8% yield) of 1-propionyl-4- (2-phenoxyethyl) semicarbazide, mp 178-183 ° C.

(c) 5-Ethyl-4- (2-phenoxyethyl) -2H-1,2,4-triazol-3 (4H) -one.

A solution of potassium hydroxide (88.4 g, 1.576 mol) in 10 liters of water is stirred and heated to 95 ° C. Next, 1-propionyl-4- (2-phenoxyethyl) semicarbazide (396.1 g, 1.576 mol) is added and the mixture is stirred at 95-96 ° C for a period of 40 minutes. Insoluble matter is collected and the filtrate

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24 is stirred in an ice bath, while 145 ml (1.74 mole) of 37% hydrochloric acid is added.

Stirring is continued with cooling to give a white solid, which is collected, rinsed with water and air dried to give 233.5 g (63.5% yield) of 5-ethyl-4- (2-phenoxyethyl) -2H- 1,2,4-triazole-3 (4H) -one, mp 136-139 ° C.

Analysis calculated for C12 H15 N3 ° 2: C, 61.79; Η »M8; N> 18.01.

Found: C, 61.77; H, 6.50; N, 17.91.

Example 6 2- [3- [4- (3-Chlorophenyl) -1-piperazinepropyl] -5-ethyl-2,4-dihydro-4- (2-phenoxyethyl) -3H-1,2,4-triazole -3-on CA Π — f / - \ / C1

CH2CH2C »2-N ^ _y-Q

ISLAND

Reaction in isopropanol with sodium hydroxide.

A mixture of 5-ethyl-4- (2-phenoxyethyl) -2H-1,2,4-triazol-3 (4H) -one (60.0 g, 0.257 mol) 1- (3-chlorophenyl) -4 - (3-chloropropyl) piperazine, hydrochloride (79.7 g, 0.257 mol) sodium hydroxide (26.7 g, 0.669 mol) and 400 ml of isopropanol are stirred and heated to reflux for a period of 10 to 18 hours. The mixture is acidified with 35 ml (0.42 mol) of 37% hydrochloric acid and the solvent is concentrated under reduced pressure. Residual material is stirred with 400 ml of methylene chloride, filtered and the filtrate is concentrated under reduced pressure. Crystallization of the residue from 600 ml of isopropanol gives 81.5 g (62.5% yield) of product which is further crystallized from water and then isopropanol to form 2- [3- [4- (3-30 chlorophenyl) -1-piperazinyl ] propyl] -5-ethyl-2,4-dihydro-4- (2-phenoxyethyl) -3H-1,2,4-triazol-3-one hydrochloride, m.p. 180-182.5 ° C.

13

Spectral analytical (NMR, C NMR, IR) and elemental analytical data are consistent and consistent with those obtained for the identical product of Example 2.

35 25

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Example 7

Further Compounds of Formula I

Using the indicated phenoxyalkyl halide in place of phenoxyoxy bromide in Example 2, alkylation of 2- [3- [4- (3-chloro-5-phenyl) -1-piperazinyl] propyl] -5-ethyl-1H-1 , 2,4-triazole-3 (2H) -one to produce the compounds indicated.

C, Hr - / - V; C1

2 J I Γ \ M

10 \ JT <C1V 3 "N ^ _J

ISLAND

Compounds Phenoxyalkyl halide 15 ..............-............................... ..............- —.......

Rj n 4-C1 2 4-chlorophenoxyethyl chloride 3- C1 2 3-chlorophenoxyethyl chloride 4-F 2 4-fluorophenoxyethyl bromide 4- F 3 4-fluorophenoxypropyl chloride 3- CH 2 O 2 3-methoxyphenoxyethyl chloride 4- CH 2 O 2 4-methoxyphenoxyethyl chloride

Example 8 4- [3- (4- (3-Chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (IIa) ) - (α, 2,3-γγ '' (a) 1- (3-Chloropropyl) -4- (3-chlorophenyl) piperazine hydrochloride.

A 50% sodium hydroxide solution (430.6 g, 5.333 mol) is added dropwise to a stirred solution of 1- (3-chlorophenyl) piperazine hydrochloride 35

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26 (502.0 g, 2.153 mol) and l-bromo-3-chloropropane (339.0 g, 2.153 mol) in 435 ml of water and 535 ml of acetone while maintaining a temperature of 0-10 ° C.

Stirring is continued for a period of 16 hours at room temperature and the upper organic phase is then separated and concentrated under reduced pressure. The residual residual oil is collected in 500 ml of acetone,. is filtered and the filtrate is concentrated under reduced pressure to an oily residue which is dissolved in boiling dilute hydrochloric acid (1.67 liters of water plus 280 ml of concentrated HCl, 3.36 mol). The oil, which initially separates from the cooled acidic solution, solidifies upon standing and is collected, rinsed with cold water and air-dried. Crystallization of this material from water using activated charcoal gives 438.4 g (66%) of 1- (3-chloropropyl) -4- (3-chlorophenyl) piperazine hydrochloride, mp 196.5-198.5 ° C. The hydrochloride salt is converted to the free base with aqueous 10% sodium hydroxide and recovered by extraction with ether 15 (dried over magnesium sulfate). Concentration of the ether extract gives 1- (3-chloropropyl) -4- (3-chlorophenyl) -piperazine free base as an oily residue.

(b) Reaction in xylene.

Sodium hydroxide (4.2 g, 0.105 mol) in 20 ml of water is added to 5-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (11.96 g, 0.105 mol), obtained according to the method of 0. Org. Chem., 41, 3233-3237 (1976) in 120 ml of ethanol.

After the addition, distillable material is removed under reduced pressure, ethanol is added to residual material and removed under reduced pressure, and the process is repeated until the sodium salt of 5-ethyl-2,4-dihydro-3H-1,2,4-triazole 3-one is obtained as a dry solid.

The sodium salt is pulverized, suspended in 600 ml of xylene and mixed with 1- (3-chloropropyl) -4- (3-chlorophenyl) piperazine free base (28.6 g, 0.105 mol). The resulting mixture is refluxed with stirring for 60 hours, 30 and the reaction mixture is filtered and concentrated under reduced pressure. Residual material is collected in 40 ml of ethanol, acidified with ethanolic hydrogen chloride and, upon standing, yields 8.7 g of solid which is further purified by crystallization from ethanol to give 6.3 g (15.5% yield) of 4- [ 3- [4- (3-Chlorophenyl) -1-piperazinyl] propyl] -5- ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride, m.p. 215 ° C.

An analytical sample, similarly prepared, melted at 210-212 ° C.

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27

Analysis calculated for C H, 6.52; N, 18.13. Found: C, 53.03; H, 6.47; N, 18.16.

NMR (DMSO-d 6): 1.17 (3H, t, 7.3 Hz); 2.09 (2H, m); 2.57 (2H, q, 7.3 Hz); 3.19 (8H, m); 3.62 (4H, m); 6.92 (3H, m); 7.23 (1H, t, 7.7 Hz); Δ 11.40 (1H, bs).

13 C NMR (ppm): 9.56, 18.36, 23.36, 37.43, 45.07, 50.51, 52.92, 113.98, 115.07, 118.91, 130.48, 133.87, 148.07, 150.90, 155.15.

(c) Reaction in acetonitrile with potassium carbonate.

A mixture of 5-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (11.3 g, 0.1 mole) 1- (3-chloropropyl) -4- (3 -chlorophenyl) piperazine (27.32 g, 0.1 mole) of powdered potassium carbonate (27.64 g, 0.2 mole) and a trace of potassium iodide in 230 ml of acetonitrile are refluxed for a period of 18 hours and filters are resuspended. Concentration of the filtrate under reduced pressure and the residual material to acid in ethanol with ethanol in hydrogen chloride forms the hydrochloride salt which is purified by crystallization from ethanol to give 11.0 g (28.6% yield) of 4- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride, mp 209-211 ° C.

20

Example 9 4- [3- [4- (3-Chlorophenyl) -1-piperazinyl] propyl] 5-ethyl-2,4-dihydro-2- (2-phenoxyethyl) -3H-1,2,4-triazole 3-on 25 ci - ^ C2H5 -p = t |

ISLAND

(A) Reaction in xylene.

Sodium hydroxide (1.2 g, 0.03 mol) in 5-10 ml of water is added to 4- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-2,4-dihydro -3H-1,2,4-triazol-3-one hydrochloride (5.8 g, 0.015 mol) in 100 ml of ethanol. After mixing 35, distillable material is removed under reduced pressure and residual material is repeatedly collected in ethanol and concentrated until dry sodium salt of 4- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5- ethyl 2,4-dihydro-3H-1,2,4-triazol-3-one is obtained as a hard solid.

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28

The sodium salt is pulverized, suspended in 100 ml of xylene and mixed with phenoxyethyl bromide (3.02 g, 0.015 mol). The resulting mixture is refluxed with stirring for a period of 60-70 hours and the hot reaction mixture is filtered and concentrated under reduced pressure to give 7.46 g of the crude free base as an oil. Purification of the free base is carried out chromatographically using a silica column with ethanol / chloroform as eluant. Free base, obtained by the chromatographic separation, is converted to the hydrochloride salt and crystallized from ethanol to give 2.8 g (37% yield) of analytically pure 4- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl ] -5-Ethyl-2,4-dihydro-2- (2-phenoxyethyl) -3H-1,2,4-triazol-3-one hydrochloride, mp 182-184 ° C.

Analysis calculated for NgOg.HCl: C, 59.29; H, 6.57; N, 13.83. Found: C, 59.37; H, 6.74; N, 13.53.

NMR (DMSO-d 6): 1.18 (3H, t, 7.2 Hz); 2.15 (2H, m); 2.62 (2H, q, 7.2 Hz); 3.18 (6H, m); 3.68 (6H, m); 4.01 (2H, t, 6.0 Hz); 4.25 (2H, t, 6.0 Hz); 6.95 (6H, m); 7.28 (3H, m); 11.70 (1H, bs).

(b) Reaction in acetonitrile with potassium carbonate.

A mixture of 4- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride (10.8 g, 0.028 mol) of phenoxyethyl bromide (5.83 g, 0.028 mol) of potassium carbonate (11.6 g, 0.084 mol) and traces of potassium iodide in 100 ml of acetonitrile is refluxed for a period of 66 hours. The hot reaction mixture is filtered, the filtrate is concentrated under reduced pressure and residual material is collected in chloroform. The chloroform solution is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 13.2 g of the free base 4- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-2 , 4-dihydro-2- (2-phenoxyethyl) -3H-1,2,4-triazol-3-one. The free base is converted to the hydrochloride salt in ethanol with ethanol in hydrogen chloride and crystallized from ethanol to give a 71% yield of analytically pure 4- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-Ethyl-2,4-di hydro-2- (2-phenoxyethyl) -3H-1,2,4-triazol-3-one hydrochloride, mp 175-177 ° C.

Analysis calculated for C 25 32 C 1 N 5 ° 2 *; C, 59.29; H, 6.57; N, 13.83. Found: C, 59.04; H, 6.61; N, 13.98.

NMR (DMSO-d6): 1.18 (3H, t, 7.2 Hz); 2.16 (2H, m); 2.62 (2H, q, 7.2 Hz); 3.18 (6H, m); 3.68 (6H, m); 4.01 (2H, t, 6.0 Hz); 4.25 (2H, t, 6.0)

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29

Hz); 6.95 (6H, m); 7.28 (3H, m); 11.70 (1H, bs).

Example 10 4- [3- [4- (3-Chlorophenyl-1-piperazinylpropyn-5-ethyl-2,4-dihydro-2- (3-5-phenoxypropyl) -3H-1,2,4-triazol-3-yl) on C1! -y C2H5 I -—i

\ J) -N. N '(C, 4 ^' N \ ^ '(CH 2) 2 "0-O

10 \ _ / Π 0

A mixture of 3-phenoxypropyl bromide (3.01 g, 0.014 mol) 4- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-2,4-dihydro-3H -1,2,4-15 triazol-3-one, hydrochloride (5.4 g, 0.014 mol) of powdered potassium carbonate (5.8 g, 0.042 mol) and traces of potassium iodide in 50 ml of acetonitrile are refluxed for a period of time. 20 hours. The hot reaction mixture is filtered, the filtrate is concentrated under reduced pressure and residual material is collected in chloroform and filtered. Solvent is removed and further purification is performed chromatographically using a silica gel column with ethanol / chloroform as eluant. The chromatographically purified material is collected in ether and acidified with ethanolic hydrogen chloride to give a solid which is triturated with ethanol to give 1.6 g (20% yield) of 4- [3- [4- (3- 1-piperazinylpropyl] -5-ethyl-2,4-dihydro-2- (3-phenoxypropyl) -3H-1,2,4-triazol-3-one dihydrochloride hydrate, mp 146-148 ° C.

Analysis calculated for C CgH Cl ClClNgOg.2HC1.0.75 Η δ: C, 54.75; H, 6.63; N, 12.28. Found: C, 55.03; H, 6.54; N, 12.49.

NMR (DMSO-d 6): 1.19 (3H, t, 7.3 Hz); 2.15 (4H, m); 2.62 (2H, q, 7.3 Hz); 3.20 (6H, m); 3.80 (8H, m); 4.01 (2H, t, 6.0 Hz); 6.96 (6H, m); 7.29 (3H, m); 7.78 (3H, bs); 11.80 (1H, bs).

35

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30

Example 11 4- [3- [4- (3-Chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-2,4-dihydro-2- (4-phenoxybutyl) -3H-1,2,4-triazole-3 on c \ _ ΓΛ _ / - \

C \ -H N- (CH,) - 1 ^^ "^ V0 \ J

0 10

A mixture of 4-phenoxybutyl chloride (2.29 g, 0.01 mole) of 4- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-2,4-dihydro-3 1,2,4-triazol-3-one hydrochloride (3.86 g, 0.01 mole) of powdered potassium carbonate (4.15 g, 0.03 mole) and traces of potassium iodide in 50 ml of acetonitrile are refluxed for 15 minutes. period of 65 hours. The hot reaction mixture is filtered, the filtrate is concentrated under reduced pressure and residual material is collected in ether and filtered. Solvent is removed and further purification is carried out chromatographically using a silica gel column with ethanol / chloroform as eluent. The chromatographically purified material is collected in ethanol and acidified with ethanolic hydrogen chloride to give 2.17 g of 4- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-2.4 -di hydro-2- (4-phenoxybutyl) -3H-1,2,4-triazol-3-one hydrochloride hydrate, m.p. 125-127 ° C.

Analysis calculated for ^HggClNgOg.HCl.1 / 4H₂O: 25 C, 60.17; H, 7.02; N, 13.00. Found: C, 60.19; H, 7.11; N, 12.89.

NMR (DMSO-d 6): 1.18 (3H, t; 7.4 Hz); 1.75 (4H, m); 2.16 (2H, m); 2.61 (2H, q, 7.4 Hz); 3.18 (6H, m); 3.80 (6H, m), 3.96 (4H, m); 6.92 (6H, m); 7.25 (3H, m); 11.75 (1H, bs).

Example 12

Exterior in past past look

By using the indicated phenoxyalkyl halide in place of phenoxyethyl bromide in Example 9, alkylation of 4- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-2,4-dihydrohydrocarbonylamide is performed. 3H-1,2,4-triazol-3-one to give the indicated compounds.

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31 c \ / -v C2ll5 —— η

\ = \ / \ I

\ J- \ / - {(: ii2> 3-n n ^ '- {cvn-0 - \ / \ _ / li 5 o

Compound Phenoxyalkyl halide 10 Rx n 4-C1 2 4-chlorophenoxyethyl chloride 3- C1 2 3-chlorophenoxyethyl chloride 4- F 2 4-fluorophenoxyethyl bromide 4-F 3 4-fluorophenoxypropyl chloride 3- CH30 2 3-methoxyphenoxyethyl chloride 4- CH methoxyphenoxyethylchlorid

Claims (6)

1. Analogous Process for Preparing a Compound of General Formula I C2U5 15 ---- ΓΝ, 4 2 »b / N \ 3 /» X WB A (B) (I) 15 wherein A is a group of formula "" - "• CKy 20 and B are a group of formula R1 o- (cs2) n- 25 \ J / and wherein Rj represents hydrogen, halogen or alkoxy of 1-4 carbon atoms, n is 2-4, R is halogen, or a pharmaceutically acceptable acid addition salt thereof, CHARACTERISTICALLY CHARACTERIZED BY CHALLENGING A COMPOUND OF THE FORMULA Vrr - * J (A ') (B (X) 35 wherein A 'represents hydrogen or the above defined groups A and B' is hydrogen or the above defined group B 10 o (ai 2) n-15 wherein R 1 has a meaning given above, n is an integer 2 to 4 and one of A 'or B' is hydrogen, with an alkylating agent of formula 20 y - - y R (IX) 25 wherein R represents halogen and X represents halogen or a suitably leaving group when A 'in Formula X is hydrogen, or an all coolant of formula 30 30 - ° C ^CH₂) 35 (VII) 34 DK 158728B wherein R1 and n have the meanings given above and X represents halogen or a when B 'in formula X is hydrogen, then a compound prepared if desired is converted into a pharmaceutically acceptable acid addition salt thereof. 5 A process according to claim 1, characterized in that R 1 represents hydrogen, n represents 2 and R is metachloro. 3. Process according to claim 1 or 2, characterized in that 2- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-2,4 is prepared from the appropriate starting materials. -di hydro-4- (2-phenoxyethyl) -3H-1,2,4-triazol-3-one. 4. A process according to claim 1 or 2, characterized in that 2- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-2,4-dihydro is prepared from the appropriate starting materials. -4- (2-phenoxyethyl} -3H-1,2,4-triazol-3-one hydrochloride. 5. A process according to claim 1 or 2, characterized in that 4- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-2,4-di is prepared from the appropriate starting materials. hydro-2- (2-phenoxyethyl) -3H-1,2,4-triazol-3-one. 6. A process according to claims 1 and 2, characterized in that 4- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-2,4-dihydro-1 is prepared from the appropriate starting materials. 2- (2-phenoxyethyl) -3H-1,2,4-triazol-3-one hydrochloride. 25 30 35